Eicosapentaenoic acid (EPA), which is an important
polyunsaturated fatty acid in fish oil, improves blood coagulability
and prevents thrombosis. EPA is usually available for treatment of
patients with obliterating arteriosclerosis in Japan, but its usefulness
for microcirculation in the foot has not been established. We studied
the effect of highly purified ethyl eicosapentaenoate on decreased
microcirculation in the foot in Japanese patients with type 2 diabetes
mellitus. Changes in ankle-brachial index (ABI), toe systolic pressure,
and toe-brachial index (TBI) with administration of EPA were
evaluated in outpatients. Individual comparison of mean values
before and after treatment was performed by using paired Student
t test. Both decreased toe systolic pressure and TBI significantly
improved with administration of ethyl eicosapentaenoate for 4 weeks
in patients who had decreased TBI; decreased TBI was normalized in
24 of 35 big toes (68.6%). In addition, treatment improved decreased
ABI; decreased ABI was normalized in 4 of 6 lower limbs (66.7%).
This study confirmed that administration of highly purified ethyl
eicosapentaenoate improves peripheral microcirculation in diabetic
patients with decreased TBI and ABI.

Disturbance of peripheral microcirculation in the lower
limbs of diabetic patients is associated with skin ulcer and/
or foot gangrene [1]. A diagnosis of Peripheral Artery Disease
(PAD) indicates a high risk of amputation in diabetic patients, but
amputation of a lower limb worsens the quality of life of these
patients. Improved peripheral microcirculation in the foot should
effectively prevent the risk of amputation.

Fish oil, which is rich in n-3 Polyunsaturated Fatty Acid
(PUFA), contains a property that prevents the development of
atherosclerosis and thrombosis [2]. Dietary supplementation
with n-3 PUFA has been reported to improve decreased Ankle-
Brachial Index (ABI) in patients with PAD [3]. Eicosapentaenoic
acid (EPA), which is an important PUFA in fish oil, improves
blood coagulability and prevents the development of thrombosis [4]. The ratio of plasma EPA to Arachidonic Acid (AA) has
been reported to be significantly decreased in patients with
PAD, indicating that a reduced ratio of plasma EPA/AA may
be involved in the development of peripheral arteriosclerosis
in these patients [5]. Highly purified EPA has been reported to
significantly reduce brachial-ankle pulse wave velocity in patients
with cardiovascular risk factors [6] or Type 2 Diabetes Mellitus
(T2DM) [7]. However, whether highly purified EPA improves
peripheral microcirculation in the toes of diabetic patients with
obliterating arteriosclerosis has not yet been investigated. The
present data demonstrate a possible improvement of peripheral
microcirculation with administration of highly purified ethyl
eicosapentaenoate in the big toes of patients with T2DM who
have a decreased blood supply in the foot.

Subjects and Design

Subjects

This study included 25 Japanese outpatients with T2DM (13
male and 12 female; age, 64.3 ± 1.7 years) who had a Toe-Brachial
Index (TBI) of less than 0.6 and therefore were considered to
have obliterating arteriosclerosis because the range of normal
TBI values is greater than 0.6 [8].

EPA is well confirmed to be clinically available for the
treatment of patients with obliterating arteriosclerosis in
Japan. After the patients provided consent, highly purified ethyl
eicosapentaenoate (Mochida Pharmaceuticals Co. Ltd., Tokyo,
Japan) was prescribed at a dosage of 900 mg twice a day (a
total of 1800 mg/day). The purity of ethyl eicosapentaenoate
is greater than 98%. The patients were treated with ethyl
eicosapentaenoate over 4 weeks.

Measurement

ABI, Toe Systolic Pressure (TSB), and TBI were measured
with the patient in a supine position on a bed by using the Forum
ABI/PWV (Omron Colin Co., Ltd., Tokyo, Japan) [9]. TSB was
measured in both big toes in each patient. ABI was calculated by
dividing calf systolic blood pressure by brachial systolic blood
pressure, and TBI was calculated by dividing big toe systolic blood pressure by brachial systolic blood pressure. TBI, TSB,
and ABI were measured before and 4 weeks after the start of
treatment with EPA, and the effects of ethyl eicosapentaenoate
were evaluated by measuring TBI, TSB, and ABI.

Statistical analysis

All data are expressed as mean ± SD. Statistical analysis was
performed by using Prism Version 4.0b computer software.
Individual comparison of the mean values before and after
treatment was performed by using paired Student t test. P < 0.05
was considered statistically significant.

Results

After treatment with ethyl eicosapentaenoate for 4 weeks, 10
patients had a significant decrease in TBI of both the right and left
big toes and 15 patients had a significant decrease in TBI of only
a single big toe (right or left). As shown in Table 1, body weight
and glycemic control did not change as a result of treatment.
Decreased TSB with decreased blood flow in the big toes of these
patients significantly increased from 72.8 mm Hg to 87.8 mm Hg,
although brachial systolic and diastolic blood pressure did not
change. Decreased TBI significantly improved from 0.48 to 0.61
and was normalized in 24 of 35 big toes (68.6%). In addition, ABI
significantly increased from 1.09 to 1.13. Although the ABI was
less than 0.9 in 6 of 35 lower limbs (17.1%) in the 35 patients with
decreased TBI before the start of the treatment, the decreased
ABI normalized in 4 of these 6 lower limbs (66.7%).

Discussion

This study showed that administration of highly purified ethyl
eicosapentaenoate for 4 weeks significantly improved decreased
TSB and TBI in Japanese patients with T2DM, independently of
glycemic control and blood pressure in the general circulation.
ABI also improved after 4 weeks of treatment. Low TSB and TBI
are important risk factors for amputation [2], so improvement
in TSB and TBI with administration of highly purified ethyl
eicosapentaenoate should contribute to the prevention of skin
ulcer and/or gangrene in the feet of patients with T2DM who
have PAD.

Table 1: Changes of metabolic parameters before and at 4 weeks after
the start of high purity ethyl icosapentatenoate administration.

The EPA/AA ratio has been reported to be significantly lower
in patients with PAD [6], but administration of highly purified
ethyl eicosapentaenoate significantly increases this ratio [10].
We have previously demonstrated a significant reduction of
plasma thrombin-antithrombin III complex with administration
of ethyl eicosapentaenoate for 4 weeks in patients with T2DM
who have albuminuria [11]. The present data showed that the
effect of ethyl eicosapentaenoate on peripheral circulation in
the toes is apparent after only 4 weeks of treatment. Therefore,
an improvement in hypercoagulability with use of highly
purified ethyl eicosapentaenoate contributes to improvement
of peripheral circulation in big toes. Furthermore, the Japan
EPA Lipid Intervetion Study (JELIS) showed that treatment with
ethyl eicosapentaenoate markedly reduced the occurrence of
coronary artery disease in patients with PAD [12]. It is supposed
that administration of highly purified ethyl eicosapentaenoate is
beneficial in patients with T2DM who have PAD.

In conclusion, highly purified ethyl eicosapentaenoate
improves peripheral microcirculation in the toes of patients with
T2DM who have decreased TBI, independently of glycemic control
and blood pressure. Administration of highly purified ethyl
eicosapentaenoate is beneficial in preventing the development
of gangrene and avoiding amputation because of gangrene in
patients with T2DM who have PAD.